The long-range objective of this project is to clarify the genetic and biochemical substructure of the hexosaminidase deficiency diseases, a group of recessively inherited lysosomal storage diseases. Using a coordinated clinical, genetic, and biochemical program we are trying to determine a) How many subunits (or distinct genetic loci) are required for the hexosaminidase enzyme? b) Which enzyme subunit is the site of the mutational alteration in the various hexosaminidase deficiency diseases due to structural gene mutations? and c) How does the mutational alteration of an enzyme subunit affect the enzyme protein to reduce its activity? At least 12 hexosaminidase deficiency diseases are known, 3 of which were discovered in our laboratory. We are studying 4 of these in patients and carriers using a variety of techniques including 1) fractionation of hexosaminidases 2) studying the abnormal residual hexosaminidases for abnormal properties 3) somatic cell hybridization and 4) natural substrate studies. Our preliminary evidence suggests that three of these disorders may be beta-subunit disordrs and one an alpha-subunit disorder. One disorder appears to be the result of defective subunit binding. Abnormal hexosaminidase has been found in two disorders. We propose to extend these studies to all four new hexosaminidase disorders and ultimately to all hexosaminidase deficiency diseases. In this way it may be possible to incorporate these disorders into a multiple loci-multiple alleles system as has been done with the hemoglobinopathies. And it may be possible to show for each disorder how the mutation causes a reduction in enzyme activity.